6-O-Methylerythromycin A (Clarithromycin) of Formula I, is a second-generation semi-synthetic macrolide antibiotic and exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, mycoplasma, and chlamydia. Furthermore, it has greater stability at physiological pH, which renders it as a superior alternative to its parent compound, erythromycin. Clarithromycin is a useful therapy for infections of the upper and lower respiratory tract, for infections due to chlamydia, mycoplasma and legionella, for infections of soft tissue, and for the eradication of H. Pylori (when used in combination with acid suppressing agents).
The critical step in the synthesis of clarithromycin is the selective methylation of 6-hydroxy position of erythromycin A of Formula II, since erythromycin A has many hydroxy groups. In U.S. Pat. No. 4,331,803, there is described a method for methylating the hydroxy group at the 6-position of erythromycin A derivatives, with a methylating agent in the presence of a base in a polar solvent. By following this method one gets compounds which are methylated at hydroxy groups other than the 6-position along with the 6-0-methyl form and therefore, requires a good purification technique to get the intended 6-0-methyl form which reduces the yield drastically.
Another method described in U.S. Pat. No. 4,672,109 for carrying out the selective methylation recommends use of a polar aprotic solvent such as dimethyl sulphoxide (DMSO), N, N-dimethylformamide (DMF), hexamethylphosphoric triamide, a mixture consisting of two or more of these solvents, or a mixture consisting of one of these solvents and tetrahydrofuran. The most preferred example of the solvents in the prior art is the mixture of DMSO and tetrahydrofuran for affecting the desired methylation followed by quenching with aqueous dimethylamine solution and extraction with hexanes.
A major limitation of the above procedure from a commercial view point, is that recovery of tetrahydrofuran which becomes extremely difficult to accomplish as it distributes almost equally, among both the aqueous dimethylsulphoxide and hexane layers and forms a constant boiling azeotrope with hexanes. Tetrahydrofuran is an expensive solvent and adds a significant cost factor in the overall cost of production of clarithromycin. Hence, non-accomplishment of the recovery of tetrahydrofuran makes the said process costly and renders it unattractive on a commercial scale. Moreover, the use of solvent tetrahydrofuran is burdened with the risk of fire and explosion.